Transforming growth factor xcex2 (TGF-xcex2) is a family of 25-kDa structurally homologous dimeric proteins containing one interchain disulfide bond and four intrachain disulfide bonds. The TGF-xcex2 family is composed of three-known members (TGF-xcex21, TGF-xcex22, and TGF-xcex23) in mammalian species. TGF-xcex2 is a bifunctional growth regulator: it is a growth inhibitor for epithelial cells, endothelial cells, T-cells, and other cell types and a mitogen for mesenchymal cells. TGF-xcex2 also has other biological activities, including stimulation of collagen, fibronectin, and plasminogen activator inhibitor 1 (PAI-1) synthesis, stimulation of angiogenesis, and induction of differentiation in several cell lineages.
TGF-xcex2 has been implicated in the pathogenesis of various diseases such as intimal hyperplasia following angioplasty, tissue fibrosis, and glomerulonephritis. Neutralizing antibodies to TGF-xcex2 have been used experimentally to reduce scarring of wounds, to prevent lung injury in adult respiratory distress syndrome (ARDS), and to block restenosis following angioplasty in animal models. These promising results warrant the development of TGF-xcex2 antagonists (inhibitor) that might be useful in inhibiting, ameliorating or reversing the effects of TGF-xcex2 and treating diseases.
A method of inhibiting, ameliorating or reversing the effects of TGF-xcex2 in biological systems, comprising the step of exposing said biological systems with a binding agent, said binding agent is a peptide which substantially resembles a segment of the TGF-xcex2 molecules.
The binding agent is a peptide which substantially resembles an active site of the TGF-xcex2 molecules, hereinafter referred to as active site peptide.
The binding agent may be in the form of a peptide or other chemical agents which substantially resembles an active site of the TGF-xcex2 molecule, the binding agents occupy the TGF-xcex2 cellular receptors making the TGF-xcex2 cellular receptors unavailable for the binding of TGF-xcex2 molecules.
The biological systems may be either in-vitro or in-vivo.
Most preferably, the binding agent of TGF-xcex2 substantially corresponds to a peptide having an amino acid sequence substantially extending from residue 41 to residue 65 of TGF-xcex2 amino acid sequence. Most preferably, said binding agents correspond to an amino acid sequence motif preferably represented by WSXD (SEQ ID NO:10) and/or RSXD (SEQ ID NO:11), wherein X represents any amino acid.
Yet another object of the present invention is to provide an active site of TGF-xcex2 molecules. And to provide an amino acid sequence which substantially represents an active site of TGF-xcex2 molecules.
Yet another object of the present invention is to provide an agonist of TGF-xcex2 molecules, comprising a carrier molecule have a plurality of said binding agent. Furthermore, a method of producing an agonist of TGF-xcex2 molecules, comprising the step of conjugating a plurality of said binding agents to a carrier molecule.